pulmonary complications of sickle cell

review article

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 359;21 www.nejm.org november 20, 20082254

Mechanisms of Disease

Pulmonary Complications of Sickle Cell Disease

Mark T. Gladwin, M.D., and Elliott Vichinsky, M.D.

From the Division of Pulmonary, Allergy, and Critical Care Medicine and the Hemo-stasis and Vascular Biology Research In-stitute, University of Pittsburgh, Pitts-burgh, (M.T.G.); and Children’s Hospital and Research Center at Oakland, Oakland, CA (E.V.). Address reprint requests to Dr. Gladwin at the Division of Pulmonary, Allergy, and Critical Care Medicine, Uni-versity of Pittsburgh, NW 168 Montefiore Hospital, 354 Fifth Ave., Pittsburgh, PA, 15213, or at [email protected].

N Engl J Med 2008;359:2254-65.Copyright © 2008 Massachusetts Medical Society.

The inheritance of two copies of a mutant β-globin gene, one from each parent, is the underlying cause of sickle cell disease. The muta-tion, GAG→GTG, substitutes valine for glutamic acid at position 6 in the

β-globin chain of hemoglobin A, resulting in a hemoglobin called hemoglobin S.1-3 Sickle cell disease is one of the most common autosomal recessive disorders in the world. Approximately 8% of black Americans are heterozygous and have the sickle cell trait, whereas approximately 1 in 600 is homozygous and has sickle cell dis-ease. In certain areas of sub-Saharan Africa, an estimated 40 to 60% of the popu-lation is heterozygous, suggesting that 1 to 4% of babies born in this region have the disease.4

Hemoglobin S polymerizes on deoxygenation. The polymers make the erythro-cyte rigid, distort its shape, and cause structural damage in the red-cell membrane, all of which alter the rheologic properties of the cell, impair blood flow through the microvasculature, and lead to hemolysis and vaso-occlusive episodes.2,5 The extent of hemoglobin S polymerization is a primary determinant of the severity of sickle cell disease6 and is proportional to the degree and duration of hemoglobin deoxy-genation and to the concentration of intracellular hemoglobin S raised to approxi-mately the 15th power.2 The presence of fetal hemoglobin in the erythrocyte re-duces the concentration of hemoglobin S and thereby inhibits its polymerization.7

The complications of sickle cell disease are myriad, but the two most common acute events are vaso-occlusive pain crisis, caused by physical and adhesive entrap-ment of red cells containing hemoglobin S in the microcirculation, and the acute chest syndrome, a lung injury syndrome.8,9 In addition, affected adults are at risk for a progressive vasculopathy, characterized by systemic and pulmonary hyperten-sion, endothelial dysfunction, and proliferative changes in the intima and smooth muscle of blood vessels.10-16 With increasing age, chronic end-organ complications begin to appear. These include chronic renal failure, hemorrhagic and nonhemor-rhagic stroke, avascular necrosis of bone, and pulmonary hypertension, which has a remarkably high prevalence among adults with sickle cell disease.12,17 From a clinical perspective, pulmonary complications — namely, the acute chest syndrome and pulmonary hypertension — are the most common causes of death in patients with sickle cell disease.8,9,12,18

Advances in our understanding of the mechanism of vaso-occlusion and the sequelae of chronic intravascular hemolysis have led to insights into the highly variable clinical manifestations of sickle cell disease. We present a new formulation of sickle cell disease and propose that certain of its complications are driven by the vaso-occlusive process, whereas others result from the deleterious effects of intravascular hemolysis on endothelial-cell and vascular function.

The New England Journal of Medicine Downloaded from www.nejm.org by CHRISTIAN ABRAHIM on November 18, 2010. For personal use only. No other uses without permission.

Copyright © 2008 Massachusetts Medical Society. All rights reserved.


n engl j med 359;21 www.nejm.org november 20, 2008 2255

Pheno t y pes of Sick le Cell Dise a se

All patients with sickle cell disease have the same GAG→GTG substitution, but the penetrance and severity of specific complications arising from the mutant hemoglobin S gene, as well as the risk factors for these complications and the age at which they occur, are highly variable. For exam-ple, the major laboratory risk factors for both vaso-occlusive pain crisis and the acute chest syn-drome are high, steady-state leukocyte counts and high hemoglobin levels.1,8,9 In contrast, chole-lithiasis, cutaneous leg ulceration, priapism, and pulmonary hypertension are associated with low steady-state hemoglobin levels and an increased rate of intravascular hemolysis.12,17,19-23 These lat-ter complications also occur in other hemolytic diseases. For example, pulmonary hypertension is common in thalassemia even though the acute chest syndrome does not occur in that disorder, which is not caused by hemoglobin S.24-28 Pria-pism and cutaneous leg ulceration also occur in other hemolytic disorders, although to a lesser ex-tent than in sickle cell disease.21,29-34

Given the divergent clinical manifestations of and epidemiologic risk factors for vaso-occlusive pain crisis and the acute chest syndrome (as com-pared with other vasculopathic complications, such as sudden death, pulmonary hypertension, cutaneous leg ulceration, and priapism), sickle cell disease may be best understood as the inter-action of two overlapping subphenotypes driven by two major mechanisms: vaso-occlusion and hemolytic anemia (Fig. 1).

Va so - o cclusion

Vaso-occlusive crises are recurrent episodes of severe pain in sickle cell disease. The cause of these events is microvascular entrapment of eryth-rocytes and leukocytes, which obstruct blood flow and bring about organ ischemia. In the microcir-culation of transgenic mouse models of sickle cell disease, hypoxia or inflammatory agents, such as tumor necrosis factor α or lipopolysac-charide, increase adhesive interactions between endothelium, leukocytes, and erythrocytes in the postcapillary venules, thereby initiating vascular occlusion.35-39 This model indicates that cycles of ischemia and reperfusion, in addition to intra-

vascular hemolysis, cause oxidant stress, in which there is activation of vascular oxidases,40-42 and inflammatory stress, which is characterized by the expression of endothelial-cell adhesion molecules and inflammatory cytokines and by leukocyto-sis.35,37,43-45 Precapillary obstruction by rigid, de-formed erythrocytes with a high content of hemo-globin S polymer probably also contributes to occlusion of the microcirculation (Fig. 1).46

Bone marrow and periosteal ischemia and reperfusion instigate cellular injury, infarction, tissue necrosis, edema, and inflammation. The clinical manifestations of these microvascular events are explosive episodes of pain and inflam-mation, often accompanied by fever and leuko-cytosis and sometimes by bone marrow necrosis, with pulmonary emboli consisting of necrotic marrow fat and cellular elements.1,8,9 Epidemio-logic studies of the frequency and severity of vaso-occlusive crises indicate an association with high concentrations of hemoglobin S, low concentra-tions of fetal hemoglobin, and high steady-state leukocyte counts and hemoglobin levels.8 These epidemiologic data point to polymerized hemo-globin S, inflammation, and hyperviscosity as ma-jor determinants of the severity of erythrocyte vaso-occlusion.

The Acu te Ches t S y ndrome

The acute chest syndrome is a common form of lung injury in sickle cell disease. When severe, this syndrome is analogous to the acute respiratory distress syndrome. In a patient with sickle cell dis-ease it is generally defined by the development of a new pulmonary infiltrate that is consistent with alveolar consolidation but not atelec tasis, involv-ing at least one complete lung segment. The radio-graphic abnormality is usually accompanied by chest pain, fever, tachypnea, wheezing, or cough.9 The acute chest syndrome is the second most com-mon cause of hospitalization among patients with sickle cell disease and the leading cause of ad-mission to an intensive care unit and premature death in this patient population.8

Causes of the Acute Chest Syndrome

Three major causes of the acute chest syndrome have been proposed: pulmonary infection, em-bolization of bone marrow fat, and intravascu-lar pulmonary sequestration of sickled eryth-





rocytes, resulting in lung injury and infarction (Fig. 2).

Pulmonary InfectionThe most common cause of the acute chest syn-drome in children and adults is pulmonary infec-tion by a community-acquired pathogen, which incites an excessive inflammatory response to what often should have been a mild upper respi-ratory infection. Studies have shown that trans-genic mice that express human hemoglobin S are susceptible to inflammatory triggers such as lipo-

polysaccharide and episodic exposure to environ-mental hypoxia, with the development of lung injury at doses of endotoxin or degrees of hypoxia that do not adversely affect wild-type mice.47,48

The National Acute Chest Syndrome Study Group analyzed 671 episodes of the acute chest syndrome in 538 patients with sickle cell disease to determine the cause, outcome, and response to therapy.9 Respiratory airway sputum and bron-choalveolar-lavage specimens were analyzed for viral and bacterial infections, and an infectious agent was identified in 54% of patients who

Hemolysis, endothelial dysfunction

Precapillary arterioleSmooth-muscle

cells

Postcapillary venule

Capillary

Erythrocyte

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α4β1

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Pain crisisAcute chest syndrome

Osteonecrosis

Decreased NObioactivity

Increasedvaso-occlusion

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Figure 1. Hypothetical Mechanisms of Clinical Subphenotypes of Sickle Cell Disease.

It is hypothesized that many of the complications of sickle cell disease can be divided into two overlapping subtypes, each driven by dis-tinct mechanisms. Cutaneous leg ulceration, priapism, pulmonary hypertension, sudden death, and stroke are associated with low steady-state hemoglobin (Hb) levels and an increased rate of intravascular hemolysis, shown on the left side of the figure. These vasculopathic complications probably result from endothelial dysfunction, mediated by both inactivation of nitric oxide (NO) by free-plasma hemoglo-bin and vascular reactive oxygen species as well as arginine (Arg) catabolism by plasma arginase. This process of hemolysis-associated endothelial dysfunction may also cause hemostatic activation and intimal and smooth-muscle proliferation. Such clinical complications as vaso- occlusive pain crisis, the acute chest syndrome, avascular necrosis of bones, and retinal vasculopathy are associated with high steady-state leukocyte counts and high hemoglobin levels. These complications are likely to result from obstruction of capillaries and postcapillary venules by erythrocytes containing polymerized hemoglobin S and by leukocytes (a monocyte is shown), as shown on the right side of the figure. ET-1 denotes endothelin 1, NOS nitric oxide synthase, O2

− superoxide, VCAM-1 vascular-cell adhesion molecule 1, and XO xanthine oxidase.





were admitted to a hospital. Most of the agents were atypical bacteria and viruses. Community-acquired encapsulated bacteria were isolated in less than 10% of cases, even though normal splenic phagocytic function is rare in sickle cell disease.

Fat EmboliThe second major cause of the acute chest syn-drome is the fat emboli syndrome. It is associated

with a severe vaso-occlusive pain crisis involving multiple bones, especially the pelvis and femur, which results in infarction and edema of the bone marrow. The bone marrow undergoes ne-crosis, and its contents, including fat, cells, and even bony spicules, are released into the blood-stream and travel to the lung, where they cause acute pulmonary hypertension, severe lung in-flammation, and hypoxemia.49-51 Secretory phos-pholipase A2 is thought to convert bone marrow

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Increased polymerizationand erthyrocyte rigidity

Increased endothelialVCAM-1 expression

and adhesion

Increased erythrocyteadhesion in lung causing

pulmonary infarction

Acute chest syndrome

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rib and vertebral infarction

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Microvasculature occlusion and bone marrow infarction

Erythrocyte

NO

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Desaturatedhemoglobin

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Regionalhypoxia

NO

α4β1

VCAM-1

Figure 2. The Vicious Cycle of the Acute Chest Syndrome.

The acute chest syndrome is a lung injury syndrome initiated by three major triggers, all related to vaso-occlusion by sickle cells: infection, embolization of bone marrow fat, and intravascular sequestration of red cells, all of which cause lung injury and infarction. Lung injury results in ventilation–perfusion mismatch and hypoxemia, which leads to increased deoxygenation of hemoglobin S, followed by hemoglobin polymerization and erythrocyte vaso-occlu-sion, which in turn promote bone marrow infarction and pulmonary vaso-occlusion. NO denotes nitric oxide, and VCAM-1 vascular-cell adhesion molecule.





phospholipids to free fatty acids, which initiate an inflammatory response and lung injury in a process analogous to that triggered by intravenous administration of oleic acid in mouse models of the acute respiratory distress syndrome.52

Oil red O staining of lipid accumulations within alveolar macrophages is diagnostic of the fat emboli syndrome, and the lipid accumula-tions can be identified in more than 16% of cases of the acute chest syndrome in adults and chil-dren.9 A study compared induced sputum sam-ples of alveolar macrophages with samples ob-tained using bronchoalveolar lavage and found a modest but significant correlation between the two methods (r = 0.65).53 In this study, patients with lipid-laden macrophages in induced sputum samples had significantly greater extrathoracic pain, more neurologic symptoms, lower platelet counts, and higher aminotransferase levels than patients without evidence of fat emboli. The acute chest syndrome can be part of the spectrum of disorders in the systemic fat emboli syndrome. This latter syndrome should be suspected in pa-tients with abrupt multiorgan failure, rapid de-velopment of the acute respiratory distress syn-drome, acute increases in pulmonary arterial pressures, evidence of hepatic injury, alterations in mental status, seizures, prominent thrombo-cytopenia, and in rare cases, coagulopathy.54,55

Pulmonary InfarctionPulmonary infarction, or vaso-occlusion, may also contribute to the development of the acute chest syndrome. In a small number of patients, wedge-shaped lung infarction, sometimes followed by central cavitation, develops.9,56

Clinical Aspects of the Acute Chest Syndrome

In most adults with sickle cell anemia, the acute chest syndrome develops 24 to 72 hours after the onset of severe pain in the arms, legs, or chest. The acute chest syndrome is associated with marked systemic inflammation, with a mean peak temperature of 38.9°C and a mean white-cell count of 23,000 per cubic millimeter.9 Although a high steady-state hemoglobin level (without pain crisis) is a major risk factor for the acute chest syndrome, in hospitalized patients with vaso-occlusive pain crisis, an abrupt drop in the hemo-globin level (a mean decrease of 0.78 g per deci-liter from steady-state levels) and an increase in

markers of hemolysis often precede the develop-ment of the acute chest syndrome. The platelet count also falls before the onset of the acute chest syndrome; a platelet level of 200,000 per cubic millimeter or less is an independent risk factor for severe manifestations of the syndrome and is associated with increased risks of neuro-logic complications and the need for mechanical ventilation.

The mean length of hospitalization for adults with the acute chest syndrome is 10.5 days, as compared with only 3 to 4 days for uncomplicat-ed vaso-occlusive pain crisis. Mechanical ventila-tion is required in 13% of patients with the syn-drome, and 3% die. The outcome for patients on mechanical ventilation is actually quite good, with a mortality rate of only 19%, as compared with the outcome for all patients with the acute chest syndrome, for whom the mortality rate is approx-imately 30%.9 Rapid simple or exchange transfu-sion, ideally with antigen-matched blood, removes the trigger for acute lung injury — sickled erythro-cytes — allowing rapid recovery in young pa-tients.

Sickle cell disease is often accompanied by asthma. Reactive airway disease occurs in 13% or more of patients with the acute chest syndrome and in up to 53% of children between birth and the age of 9 years.9,57 Although a number of studies suggest that asthma is a risk factor for the acute chest syndrome and stroke in patients with sickle cell disease,58-60 it remains uncertain whether there is an increase in the prevalence of asthma among children with sickle cell disease in the steady state, as compared with matched controls.59,61 During steady-state sickle cell dis-ease, the major abnormality in pulmonary func-tion is a restrictive ventilatory impairment, char-acterized by a mild reduction in total lung capacity, and reduced diffusion capacity for car-bon monoxide.62,63 These abnormalities worsen with age and are associated with increases in pulmonary-artery pressures.63,64

Hemolysis, End o theli a l - Cell Dysfunc tion, a nd Va scul opath y

Catabolism of Hemoglobin

A complex biochemical and cellular system clears and detoxifies the hemoglobin that red cells re-lease into the plasma during normal oxidative and





mechanical stress.65 The hemoglobin dimer binds with an unusually high protein–protein affinity to haptoglobin.66 The resulting complex exposes a neoepitope recognized by the hemoglobin scaven-ger protein CD163, a transmembrane glycopro-tein that initiates the uptake of hemoglobin into macrophages and monocytes. The uptake of he-moglobin by these cells activates interleukin-10 and induces expression of heme oxygenase-1 and biliverdin reductase.67-69 These enzymes catabo-lize heme and signal potent antiproliferative, anti-oxidant, and antiinflammatory reactions.68-70 The downstream activities of these molecules take place in response to the oxidative and inflamma-tory effects of free heme, iron, and oxygen: the binding of haptoglobin to hemoglobin limits heme-mediated lipid peroxidation,71 biliverdin re-ductase catalytically generates NADPH and reduc-es glutathione,69 and heme oxygenase-1 generates carbon monoxide and biliverdin, both of which limit proliferative and thrombotic vascular inju-ry.68 New therapeutic approaches, such as hapto-globin infusions, inhaled carbon monoxide gas and carbon monoxide–releasing compounds, and genetic or pharmacologic induction of heme oxy-genase are being studied in animal models for the treatment of vascular injury in sickle cell disease.72

HemolysisEffect on Nitric OxideIn sickle cell disease, the hemoglobin and heme scavenging systems are saturated and over-whelmed, even in the steady state.73,74 Free plasma hemoglobin, in addition to generating reactive oxygen species, such as the hydroxyl and super-oxide radicals (through the Fenton and peroxidase and auto-oxidation chemical reactions),75,76 is also a potent scavenger of nitric oxide.74,77 Nitric oxide, which is normally produced by the endothelium, regulates basal vasodilator tone; inhibits platelet and hemostatic activation; inhibits transcriptional expression of nuclear factor κB–dependent adhe-sion molecules, such as vascular-cell adhesion molecule 1, intercellular adhesion molecule 1, and the selectins; and reduces superoxide levels through radical–radical scavenging.78-82 The half-life of nitric oxide in the blood is extremely short because of its rapid reaction with hemoglobin to form methemoglobin and nitrate.83 Actually, the vasodilator activity of nitric oxide is possible only because most hemoglobin is normally compart-

mentalized within erythrocytes. Flowing blood produces a cell-free zone along the endotheli-um; this zone and an area of nonflowing blood around the outside of the erythrocyte (called the unstirred layer) constitute major diffusion barriers against nitric oxide entry into red cells.84-86 These barriers reduce the rate at which nitric oxide reacts with intracellular hemoglobin by two to three orders of magnitude. The release of hemoglobin into plasma during hemolysis circumvents these diffusion barriers and serves as a potent inhibi-tor of all nitric oxide bioactivity, leading to a clinical state of endothelial-cell dysfunction and nitric oxide resistance.14,74,77,87-92

Effect on ArginineHemolysis also releases erythrocyte arginase 1 into plasma. Arginase metabolizes plasma arginine into ornithine, reducing the required substrate for nitric oxide synthesis and compounding the re-duction in the bioavailability of nitric oxide in sickle cell disease (Fig. 1).93 In one study, the plasma levels and enzymatic activity of arginase 1 were significantly increased in 228 patients with sickle cell disease as compared with black control subjects; moreover, arginase 1 modulated the metabolic profile of arginine by reducing argi-nine levels and increasing the production of orni-thine relative to that of citrulline.93 These abnor-malities were associated with severe pulmonary hypertension and an increased risk of death. Intra-vascular hemolysis has also been shown to be associated with reduced availability of nitric oxide and arginine in animal models and in humans with severe falciparum malaria.94,95 In the study of malaria, impairment of nitric oxide–dependent, flow-mediated vasodilatation developed and was associated with hemolysis and high levels of ar-ginase and lactate dehydrogenase.95

The Hypercoagulable State

Chronic depletion of nitric oxide and arginine may also contribute to the hypercoagulable state in hemolytic diseases. Since nitric oxide is a po-tent inhibitor of platelet activation, the depletion of nitric oxide and arginine (the substrate for ni-tric oxide synthesis) in sickle cell disease allows for platelet activation.96 Arginine consumption is compounded by increased intracellular platelet expression of arginase.97

Recent studies of sickle cell disease showed





correlations between the intrinsic rate of hemo-lysis and the levels of procoagulant factors in blood.98-100 In addition to the release of free hemoglobin, hemolysis is associated with the for-mation of red-cell microvesicles containing phos-phatidylserine, an activator of tissue factor.100,101 Patients with sickle cell disease who have func-tional asplenia and patients with thalassemia who have undergone surgical splenectomy have increased levels of plasma hemoglobin and red-cell microvesicles, which are potential mecha-nisms for the hypercoagulability associated with both diseases, with possible exacerbation by asple-nia.100

Additional support for the idea that hemolysis impairs nitric oxide signaling comes from trans-genic mouse models of sickle cell disease and spherocytosis and from mouse models of allo-immune hemolysis and malaria.42,94,102 In these models, there is impaired vasodilatation in re-sponse to nitric oxide donors and endothelial-dependent vasodilators, and pulmonary hyperten-sion and right heart failure develop.42,102

Pul mona r y H y pertension in Sick le Cell Dise a se

A major risk factor for pulmonary hypertension in sickle cell disease is the severity of hemolytic anemia, which can be determined by measuring steady-state hemoglobin levels and levels of lac-tate dehydrogenase, indirect bilirubin, and retic-ulocytes.12,19,23,103,104 An association between the development of pulmonary hypertension and the intensity of hemolytic anemia has been observed in three prospective screening studies of adults with sickle cell disease12,103,104 and in a growing number of pediatric studies.105-108 Pulmonary hypertension is a reported complication of other forms of chronic hereditary or acquired hemo-lytic anemia, including thalassemia intermedia and thalassemia major, paroxysmal nocturnal hemoglobinuria, spherocytosis, stomatocytosis, pyruvate kinase deficiency, alloimmune hemo-lytic anemia, glucose-6-phosphate dehydrogenase deficiency, unstable hemoglobin variants, and the microangiopathic hemolytic anemias.65,109 Al-though data from cohort screening studies are available only for sickle cell disease and thalas-semia, there are growing numbers of case reports and case series involving pulmonary hypertension

in other chronic hereditary and acquired hemo-lytic anemias.

Echocardiography

Three prospective screening studies using echo-cardiography have shown that 20% of adults with sickle cell disease have borderline or mild pul-monary hypertension, defined by a pulmonary artery systolic pressure greater than 35 mm Hg; 10% of these adults have moderate to severe pul-monary hypertension, defined by a pressure great-er than 45 mm Hg.12,103,104 Despite pulmonary artery systolic pressures that are much lower than those in idiopathic or hereditary pulmonary hyper-tension, in sickle cell disease borderline or mild pulmonary hypertension is associated with an extremely high risk of death.12,103,104,110-112 It re-mains to be determined whether elevations in pulmonary pressures are a marker for vasculopa-thy and a risk factor for cardiovascular death or whether the elevations contribute directly to death due to progressive or acute right heart failure. The implications of borderline elevations in pul-monary artery systolic pressure in the pediatric population remain unknown.

Adults with sickle cell disease should be screened for pulmonary hypertension with trans-thoracic Doppler echocardiography.12 The thin body habitus of these adults, along with dilated and hyperdynamic heart chambers, allows easy detection of the regurgitation of blood backward across the tricuspid valve during right ventricu-lar systole (Fig. 3). The tricuspid regurgitant jet velocity is used to estimate the right ventricular and pulmonary-artery systolic pressures (which are approximately four times the tricuspid regur-gitant jet velocity squared) after the addition of an estimate of the central venous pressure. In sickle cell disease, these estimated pulmonary systolic pressures correlate well with measure-ments obtained by means of right heart catheter-ization.12 A value of 2.5 m per second or more corresponds to an estimated pulmonary-artery systolic pressure of 35 mm Hg, which is approxi-mately 2 SD above the normal mean value; for patients less than 40 years of age, the reference value for the mean pulmonary-artery systolic pressure, estimated with the use of Doppler echo-cardiography, is 27.5±14.2 mm Hg (95% confi-dence interval [CI], 19.3 to 35.5).113 Although a more traditional definition of pulmonary hyper-





tension would be a tricuspid regurgitant jet veloc-ity of 3.0 m per second or more, values between 2.5 and 2.9 m per second are associated with an increased risk of death among patients with sickle cell disease.12,103,104 A follow-up analysis of the National Institutes of Health (NIH) pulmo-nary-hypertension screening cohort12 showed that with a tricuspid regurgitant jet velocity of 2.5 to 2.9 m per second, as compared with a velocity of less than 2.5 m per second, the rate ratio for death

was 4.4 (95% CI, 1.6 to 12.2; P<0.001), and with a velocity of 3.0 m per second or more, the rate ratio was 10.6 (95% CI, 3.3 to 33.6; P<0.001).

Brain Natriuretic Peptide

Another screening method entails measurement of plasma levels of the N-terminal fragment of the brain natriuretic peptide, released from cardio-myocytes during pressure or volume stretch.112 In pulmonary hypertension — both idiopathic and the type associated with sickle cell disease — the level of brain natriuretic peptide correlates with the degree of pulmonary vascular resistance and the risk of death (risk ratio, 5.1; 95% CI, 2.1 to 12.5; P<0.001).112 Analysis of the levels of N-ter-minal brain natriuretic peptide at study entry for patients with sickle cell disease who were en-rolled in the NIH pulmonary-hypertension screen-ing study and those enrolled in the Multicenter Study of Hydroxyurea in Sickle Cell Anemia re-vealed that approximately 30% of patients with sickle cell disease in both cohorts had elevated brain natriuretic peptide values (>160 ng per milli-liter) and, as compared with patients with lower values, had a significantly increased risk of death (2.87; 95% CI, 1.2 to 6.6; P = 0.02).112

It is clear that pulmonary pressures rise acute-ly during vaso-occlusive crisis and even more so in the acute chest syndrome.114 A recent study of 84 consecutively hospitalized patients with the syndrome showed that 13% of the patients had right heart failure. All five patients who required mechanical ventilation and all four patients who died during the study had jet velocity values of 3 m per second or greater.115 These data suggest that acute pulmonary hypertension and right heart dysfunction are major coexisting conditions in the acute chest syndrome.

Cardiac Catheterization

We suggest that patients with evidence of hemo-dynamically significant pulmonary hypertension (echocardiographic evidence of right heart dys-function or a tricuspid regurgitant jet velocity of 3.0 m per second or more) should undergo right heart catheterization to confirm the diagnosis and rule out left heart disease (pulmonary venous hypertension). Right heart catheterization in pa-tients with sickle cell disease and pulmonary hypertension reveals a hyperdynamic state simi-lar to the hemodynamics characteristic of porto-

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Figure 3. Doppler Echocardiogram Showing Increased Pulmonary-Artery Pressures (High Tricuspid Regurgitant Jet Velocity) and Right Heart Failure in a Patient with Sickle Cell Disease and Pulmonary Hypertension.

A Doppler echocardiographic tracing (Panel A) shows three measured regurgitant-jet-velocity envelopes across the tricuspid valve at values of 4.4, 4.5, and 4.5 m per second, which are consistent with a pressure gradient from ventricles to atria of approximately 80 mm Hg. A value of 2.5 m per second or more constitutes border-line or mild pulmonary-artery systolic hypertension and is a major risk factor for death among patients with sick-le cell disease. A four-chamber view of the heart (Panel B) shows right ventricular (RV) and right atrial (RA) dilata-tion and tricuspid-valve regurgitation (TR) (blue), mov-ing from RV to RA during ventricular systole. A video of this echocardiogram is available with the full text of this article at www.nejm.org. Echocardiogram and im-age cortesy of Vandana Sachdev, M.D., National Heart, Lung, and Blood Institute.





pulmonary hypertension.64,110 The mean pulmo-nary-artery pressure in patients with sickle cell disease and pulmonary-artery hypertension is ap-proximately 40 mm Hg, and pulmonary vascular resistance is approximately 250 dyn · sec · cm−5. The relatively low pulmonary vascular resistance is caused by the high cardiac output that is char-acteristic of anemia. Approximately 60% of cath-eterized patients with a tricuspid regurgitant jet velocity that is 3.0 m per second or more meet the definition of pulmonary-artery hypertension, indicating that vasculopathy primarily involves the pulmonary arterial system. In the other 40% of patients, the left ventricular end diastolic pres-sures are greater than 15 mm Hg, indicating a component of left ventricular diastolic dysfunc-tion.64 Patients with both pulmonary vascular dis-ease and echocardiographic evidence of diastolic dysfunction are at particularly high risk for death

(relative risk ratio, 12.0; 95% CI, 3.8 to 38.1; P<0.001).116

Other Mechanisms of Pulmonary Hypertension

There are mechanisms other than intravascular hemolysis that contribute to the development of pulmonary hypertension in patients with sickle cell disease, and they should be identified and treated (Table 1). Iron overload, hepatitis C, or nodular hepatic regenerative hyperplasia can cause liver dysfunction, which can lead to portopulmo-nary hypertension.12 Chronic renal failure, a com-mon complication of sickle cell disease, is an additional risk factor for the development of pul-monary hypertension.12,103 In situ thrombosis and pulmonary emboli are often identified clinically and at autopsy.15 These findings may be risk fac-tors for death, particularly among patients with functional or surgical asplenia.117 Chronic throm-boembolic pulmonary hypertension occurs in ap-proximately 5% of patients with sickle cell disease and severe pulmonary hypertension.64,118 Although it is widely held that repeated episodes of the acute chest syndrome cause pulmonary hypertension, with resulting chronic lung disease, most retro-spective and prospective studies show no asso-ciation between pulmonary hypertension and rates of the acute chest syndrome.12,103,104,107,112,119 This finding supports the view that clinical sub-phenotypes of sickle cell disease arise from diver-gent mechanisms.

A lter nati v e H y po theses

We recognize that alternative hypotheses could explain the clinical phenotypes associated with hemolytic anemia. For example, patients with severe hemolytic anemia also have bone marrow expansion and leukocytosis, suggesting that hemo-lysis may be associated with inflammation or may merely represent an index of disease severity. It is difficult to divorce the effects of hemolysis from those of anemia and oxidant stress; both can contribute directly to disease pathogenesis, inde-pendently of any direct effects of cell-free hemo-globin on vascular function.

Conclusions

Pulmonary complications — namely, the acute chest syndrome and pulmonary hypertension —

Table 1. Proposed Mechanisms Leading to Pulmonary Hypertension in Sickle Cell Disease.

Hemolytic anemia

Nitric oxide scavenging through reactions with cell-free plasma hemoglobin

Arginine catabolism to ornithine through reactions with arginase 1, released from red cells

Increased platelet activation by cell-free plasma hemoglobin

Increased levels of endothelin 1

Increased endogenous inhibition of nitric oxide synthase; increased production of methylated arginine and asymmetric dimethylarginine during hemolysis-related protein turnover

High cardiac output resulting from anemia

Hypoxia-inducible factors

Increased expression of hypoxia-inducible factor 1α mediated by tissue hypoxia

Increased levels of erythropoietin

Increased levels of endothelin 1

Increased levels of vascular endothelial growth factor

Anemia-related inhomogeneous ventilation–perfusion resulting from vascular instability

Perfusion dysregulation, altering ventilation–perfusion matching

Hypoxemia

Systemic factors

Oxidant stress mediated by iron-overload, free iron, and heme

Renal failure

Increased levels of uric acid

Asplenia (autoinfarction or surgical removal), leading to thrombosis as a result of increased circulating plasma hemoglobin and microparticles, thrombocytosis, and increased red-cell phosphatidylserine, which may activate tissue factor





are the leading complications associated with death in adults with sickle cell disease. In patients who die of the acute chest syndrome, abrupt in-creases in pulmonary pressures and right heart failure are common, indicating a major interac-tion between these clinical entities. The current treatment of these complications is based on lim-ited evidence or expert opinion, highlighting the critical need for randomized clinical trials in this area. Identification, prevention, and expert man-

agement of these complications by hematologists and pulmonologists will be a challenge as the population of patients with sickle cell disease ages and increases worldwide.

Dr. Gladwin reports receiving grant support from the U.S. government and INO Therapeutics in the form of a Collaborative Research and Development Agreement, from the Intramural Research Division of the National Heart, Lung, and Blood Insti-tute, and from the Institute for Transfusion Medicine and the Hemophilia Center of Western Pennsylvania. No other potential conflict of interest was reported.

References

Platt OS. The acute chest syndrome of 1. sickle cell disease. N Engl J Med 2000; 342:1904-7. [Erratum, N Engl J Med 2000; 343:591.]

Bunn HF. Pathogenesis and treatment 2. of sickle cell disease. N Engl J Med 1997; 337:762-9.

Steinberg MH. Management of sickle 3. cell disease. N Engl J Med 1999;340:1021-30.

Aliyu ZY, Gordeuk V, Sachdev V, et al. 4. Prevalence and risk factors for pulmonary artery systolic hypertension among sickle cell disease patients in Nigeria. Am J He-matol 2008;83:485-90.

Noguchi CT, Schechter AN, Rodgers 5. GP. Sickle cell disease pathophysiology. Baillieres Clin Haematol 1993;6:57-91.

Brittenham GM, Schechter AN, Nogu-6. chi CT. Hemoglobin S polymerization: primary determinant of the hemolytic and clinical severity of the sickling syndromes. Blood 1985;65:183-9.

Noguchi CT, Rodgers GP, Serjeant G, 7. Schechter AN. Levels of fetal hemoglobin necessary for treatment of sickle cell dis-ease. N Engl J Med 1988;318:96-9.

Platt OS, Brambilla DJ, Rosse WF, et al. 8. Mortality in sickle cell disease: life ex-pectancy and risk factors for early death. N Engl J Med 1994;330:1639-44.

Vichinsky EP, Neumayr LD, Earles AN, 9. et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med 2000;342:1855-65. [Erratum, N Engl J Med 2000;343:824.]

Pegelow CH, Colangelo L, Steinberg M, 10. et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hyperten-sion in sickle cell anemia. Am J Med 1997; 102:171-7.

Ohene-Frempong K, Weiner SJ, Sleeper 11. LA, et al. Cerebrovascular accidents in sickle cell disease: rates and risk factors. Blood 1998;91:288-94.

Gladwin MT, Sachdev V, Jison ML, et 12. al. Pulmonary hypertension as a risk fac-tor for death in patients with sickle cell disease. N Engl J Med 2004;350:886-95.

Gladwin MT, Schechter AN, Ognibene 13. FP, et al. Divergent nitric oxide bioavail-

ability in men and women with sickle cell disease. Circulation 2003;107:271-8.

Eberhardt RT, McMahon L, Duffy SJ, 14. et al. Sickle cell anemia is associated with reduced nitric oxide bioactivity in periph-eral conduit and resistance vessels. Am J Hematol 2003;74:104-11.

Haque AK, Gokhale S, Rampy BA, Ad-15. egboyega P, Duarte A, Saldana MJ. Pulmo-nary hypertension in sickle cell hemoglo-binopathy: a clinicopathologic study of 20 cases. Hum Pathol 2002;33:1037-43.

Kato GJ, Hsieh M, Machado R, et al. 16. Cerebrovascular disease associated with sickle cell pulmonary hypertension. Am J Hematol 2006;81:503-10.

Kato GJ, Gladwin MT, Steinberg MH. 17. Deconstructing sickle cell disease: reap-praisal of the role of hemolysis in the de-velopment of clinical subphenotypes. Blood Rev 2007;21:37-47.

Perronne V, Roberts-Harewood M, 18. Bachir D, et al. Patterns of mortality in sickle cell disease in adults in France and England. Hematol J 2002;3:56-60.

Kato GJ, McGowan V, Machado RF, et 19. al. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resis-tance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood 2006;107:2279-85.

Nolan VG, Adewoye A, Baldwin C, et 20. al. Sickle cell leg ulcers: associations with haemolysis and SNPs in Klotho, TEK and genes of the TGF-beta/BMP pathway. Br J Haematol 2006;133:570-8.

Nolan VG, Baldwin C, Ma Q, et al. 21. Association of single nucleotide polymor-phisms in klotho with priapism in sickle cell anaemia. Br J Haematol 2005;128:266-72.

Nolan VG, Wyszynski DF, Farrer LA, 22. Steinberg MH. Hemolysis-associated pri-apism in sickle cell disease. Blood 2005; 106:3264-7.

Kato GJ, Onyekwere OC, Gladwin MT. 23. Pulmonary hypertension in sickle cell dis-ease: relevance to children. Pediatr Hema-tol Oncol 2007;24:159-70.

Aessopos A, Farmakis D, Karagiorga 24. M, et al. Cardiac involvement in thalas-

semia intermedia: a multicenter study. Blood 2001;97:3411-6.

Du ZD, Roguin N, Milgram E, Saab K, 25. Koren A. Pulmonary hypertension in pa-tients with thalassemia major. Am Heart J 1997;134:532-7.

Aessopos A, Stamatelos G, Skoumas V, 26. Vassilopoulos G, Mantzourani M, Louko-poulos D. Pulmonary hypertension and right heart failure in patients with beta-thalassemia intermedia. Chest 1995;107: 50-3.

Derchi G, Fonti A, Forni GL, et al. Pul-27. monary hypertension in patients with thalassemia major. Am Heart J 1999;138: 384.

Morris CR, Kuypers FA, Kato GJ, et al. 28. Hemolysis-associated pulmonary hyper-tension in thalassemia. Ann N Y Acad Sci 2005;1054:481-5.

Burnett AL, Bivalacqua TJ. Glucose-6-29. phosphate dehydrogenase deficiency: an etiology for idiopathic priapism? J Sex Med 2008;5:237-40.

Prabhakaran K, Jacobs BL, Smaldone 30. MC, Franks ME. Stuttering priapism asso-ciated with hereditary spherocytosis. Can J Urol 2007;14:3702-4.

Thuret I, Bardakdjian J, Badens C, et al. 31. Priapism following splenectomy in an un-stable hemoglobin: hemoglobin Olmsted beta 141 (H19) Leu→Arg. Am J Hematol 1996;51:133-6.

Mohamed N, Jackson N. Severe thalas-32. saemia intermedia: clinical problems in the absence of hypertransfusion. Blood Rev 1998;12:163-70.

Taher A, Isma’eel H, Cappellini MD. 33. Thalassemia intermedia: revisited. Blood Cells Mol Dis 2006;37:12-20.

Vanscheidt W, Leder O, Vanscheidt E, 34. et al. Leg ulcers in a patient with sphero-cytosis: a clinicopathological report. Der-matologica 1990;181:56-9.

Frenette PS. Sickle cell vaso-occlusion: 35. multistep and multicellular paradigm. Curr Opin Hematol 2002;9:101-6.

Turhan A, Weiss LA, Mohandas N, 36. Coller BS, Frenette PS. Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm. Proc Natl Acad Sci U S A 2002;99:3047-51.





Belcher JD, Bryant CJ, Nguyen J, et al. 37. Transgenic sickle mice have vascular in-flammation. Blood 2003;101:3953-9.

Belcher JD, Marker PH, Weber JP, Heb-38. bel RP, Vercellotti GM. Activated mono-cytes in sickle cell disease: potential role in the activation of vascular endothelium and vaso-occlusion. Blood 2000;96:2451-9.

Osarogiagbon UR, Choong S, Belcher 39. JD, Vercellotti GM, Paller MS, Hebbel RP. Reperfusion injury pathophysiology in sickle transgenic mice. Blood 2000;96: 314-20.

Aslan M, Ryan TM, Adler B, et al. 40. Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease. Proc Natl Acad Sci U S A 2001;98: 15215-20.

Wood KC, Hebbel RP, Granger DN. 41. Endothelial cell NADPH oxidase mediates the cerebral microvascular dysfunction in sickle cell transgenic mice. FASEB J 2005; 19:989-91.

Hsu LL, Champion HC, Campbell-Lee 42. SA, et al. Hemolysis in sickle cell mice causes pulmonary hypertension due to global impairment in nitric oxide bioavail-ability. Blood 2007;109:3088-98. [Erratum, Blood 2008;111:1772.]

Kaul DK, Hebbel RP. Hypoxia/reoxy-43. genation causes inflammatory response in transgenic sickle mice but not in nor-mal mice. J Clin Invest 2000;106:411-20. [Erratum, J Clin Invest 2000;106:715.]

Belcher JD, Mahaseth H, Welch TE, et 44. al. Critical role of endothelial cell activa-tion in hypoxia-induced vasoocclusion in transgenic sickle mice. Am J Physiol Heart Circ Physiol 2005;288:H2715-H2725.

Platt OS. Sickle cell anemia as an in-45. flammatory disease. J Clin Invest 2000;106: 337-8.

Hiruma H, Noguchi CT, Uyesaka N, 46. Schechter AN, Rodgers GP. Contributions of sickle hemoglobin polymer and sickle cell membranes to impaired filterability. Am J Physiol 1995;268:H2003-H2008.

Holtzclaw JD, Jack D, Aguayo SM, Eck-47. man JR, Roman J, Hsu LL. Enhanced pul-monary and systemic response to endo-toxin in transgenic sickle mice. Am J Respir Crit Care Med 2004;169:687-95.

Sabaa N, de Franceschi L, Bonnin P, et 48. al. Endothelin receptor antagonism pre-vents hypoxia-induced mortality and mor-bidity in a mouse model of sickle-cell disease. J Clin Invest 2008;118:1924-33.

Case Records of the Massachusetts 49. General Hospital (Case 34-1997). N Engl J Med 1997;337:1293-301.

Case Records of the Massachusetts 50. General Hospital (Case 52-1983). N Engl J Med 1983;309:1627-36.

Gladwin MT, Rodgers GP. Pathogene-51. sis and treatment of acute chest syndrome of sickle-cell anaemia. Lancet 2000;355: 1476-8.

Styles LA, Schalkwijk CG, Aarsman 52. AJ, Vichinsky EP, Lubin BH, Kuypers FA. Phospholipase A2 levels in acute chest

syndrome of sickle cell disease. Blood 1996;87:2573-8.

Lechapt E, Habibi A, Bachir D, et al. 53. Induced sputum versus bronchoalveolar lavage during acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med 2003;168:1373-7.

Vichinsky E, Williams R, Das M, et al. 54. Pulmonary fat embolism: a distinct cause of severe acute chest syndrome in sickle cell anemia. Blood 1994;83:3107-12.

Castro O. Systemic fat embolism and 55. pulmonary hypertension in sickle cell dis-ease. Hematol Oncol Clin North Am 1996; 10:1289-303.

Bellet PS, Kalinyak KA, Shukla R, Gel-56. fand MJ, Rucknagel DL. Incentive spirom-etry to prevent acute pulmonary compli-cations in sickle cell diseases. N Engl J Med 1995;333:699-703.

Bryant R. Asthma in the pediatric sick-57. le cell patient with acute chest syndrome. J Pediatr Health Care 2005;19:157-62.

Boyd JH, Macklin EA, Strunk RC, De-58. Baun MR. Asthma is associated with acute chest syndrome and pain in children with sickle cell anemia. Blood 2006;108:2923- 7.

Knight-Madden JM, Forrester TS, Lewis 59. NA, Greenough A. Asthma in children with sickle cell disease and its association with acute chest syndrome. Thorax 2005; 60:206-10.

Nordness ME, Lynn J, Zacharisen MC, 60. Scott PJ, Kelly KJ. Asthma is a risk factor for acute chest syndrome and cerebral vascular accidents in children with sickle cell disease. Clin Mol Allergy 2005;3:2.

Sylvester KP, Patey RA, Broughton S, 61. et al. Temporal relationship of asthma to acute chest syndrome in sickle cell disease. Pediatr Pulmonol 2007;42:103-6.

Field JJ, Glassberg J, Gilmore A, et al. 62. Longitudinal analysis of pulmonary func-tion in adults with sickle cell disease. Am J Hematol 2008;83:574-6.

Klings ES, Wyszynski DF, Nolan VG, 63. Steinberg MH. Abnormal pulmonary func-tion in adults with sickle cell anemia. Am J Respir Crit Care Med 2006;173:1264-9.

Anthi A, Machado RF, Jison ML, et al. 64. Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension. Am J Respir Crit Care Med 2007;175:1272-9.

Rother RP, Bell L, Hillmen P, Gladwin 65. MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemo-globin: a novel mechanism of human dis-ease. JAMA 2005;293:1653-62.

Nagel RL, Gibson QH. The binding of 66. hemoglobin to haptoglobin and its rela-tion to subunit dissociation of hemoglo-bin. J Biol Chem 1971;246:69-73.

Kristiansen M, Graversen JH, Jacob-67. sen C, et al. Identification of the haemo-globin scavenger receptor. Nature 2001; 409:198-201.

Ryter SW, Otterbein LE, Morse D, Choi 68. AM. Heme oxygenase/carbon monoxide

signaling pathways: regulation and func-tional significance. Mol Cell Biochem 2002;234-235:249-63.

Baranano DE, Rao M, Ferris CD, Sny-69. der SH. Biliverdin reductase: a major physiologic cytoprotectant. Proc Natl Acad Sci U S A 2002;99:16093-8.

Otterbein LE, Bach FH, Alam J, et al. 70. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 2000;6: 422-8.

Melamed-Frank M, Lache O, Enav BI, 71. et al. Structure-function analysis of the antioxidant properties of haptoglobin. Blood 2001;98:3693-8.

Belcher JD, Mahaseth H, Welch TE, 72. Otterbein LE, Hebbel RP, Vercellotti GM. Heme oxygenase-1 is a modulator of in-flammation and vaso-occlusion in trans-genic sickle mice. J Clin Invest 2006;116: 808-16.

Bensinger TA, Gillette PN. Hemolysis 73. in sickle cell disease. Arch Intern Med 1974;133:624-31.

Reiter CD, Wang X, Tanus-Santos JE, 74. et al. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002;8:1383-9.

Hebbel RP. Auto-oxidation and a mem-75. brane-associated ‘Fenton reagent’: a possi-ble explanation for development of mem-brane lesions in sickle erythrocytes. Clin Haematol 1985;14:129-40.

Repka T, Hebbel RP. Hydroxyl radical 76. formation by sickle erythrocyte mem-branes: role of pathologic iron deposits and cytoplasmic reducing agents. Blood 1991;78:2753-8.

Reiter CD, Gladwin MT. An emerging 77. role for nitric oxide in sickle cell disease vascular homeostasis and therapy. Curr Opin Hematol 2003;10:99-107.

Furchgott RF, Zawadzki JV. The oblig-78. atory role of endothelial cells in the relax-ation of arterial smooth muscle by acetyl-choline. Nature 1980;288:373-6.

Ignarro LJ, Buga GM, Wood KS, Byrns 79. RE, Chaudhuri G. Endothelium-derived re-laxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A 1987;84:9265-9.

Palmer RM, Ashton DS, Moncada S. 80. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 1988;333: 664-6.

Panza JA, Casino PR, Kilcoyne CM, 81. Quyyumi AA. Role of endothelium-derived nitric oxide in the abnormal endothelium-dependent vascular relaxation of patients with essential hypertension. Circulation 1993;87:1468-74.

De Caterina R, Libby P, Peng HB, et al. 82. Nitric oxide decreases cytokine-induced endothelial activation: nitric oxide selec-tively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60-8.

Doherty DH, Doyle MP, Curry SR, et al. 83. Rate of reaction with nitric oxide deter-





mines the hypertensive effect of cell-free hemoglobin. Nat Biotechnol 1998;16:672- 6.

Butler AR, Megson IL, Wright PG. 84. Diffusion of nitric oxide and scavenging by blood in the vasculature. Biochim Bio-phys Acta 1998;1425:168-76.

Liu X, Miller MJ, Joshi MS, Sadowska-85. Krowicka H, Clark DA, Lancaster JR Jr. Diffusion-limited reaction of free nitric oxide with erythrocytes. J Biol Chem 1998; 273:18709-13.

Schechter AN, Gladwin MT. Hemo-86. globin and the paracrine and endocrine functions of nitric oxide. N Engl J Med 2003;348:1483-5.

Yu B, Raher MJ, Volpato GP, Bloch 87. KD, Ichinose F, Zapol WM. Inhaled nitric oxide enables artificial blood transfusion without hypertension. Circulation 2008; 117:1982-90.

Minneci PC, Deans KJ, Zhi H, et al. 88. Hemolysis-associated endothelial dysfunc-tion mediated by accelerated NO inactiva-tion by decompartmentalized oxyhemo-globin. J Clin Invest 2005;115:3409-17.

Gladwin MT. Deconstructing endo-89. thelial dysfunction: soluble guanylyl cy-clase oxidation and the NO resistance syndrome. J Clin Invest 2006;116:2330-2.

Nath KA, Shah V, Haggard JJ, et al. 90. Mechanisms of vascular instability in a transgenic mouse model of sickle cell dis-ease. Am J Physiol Regul Integr Comp Physiol 2000;279:R1949-R1955.

Kaul DK, Liu XD, Chang HY, Nagel 91. RL, Fabry ME. Effect of fetal hemoglobin on microvascular regulation in sickle trans-genic-knockout mice. J Clin Invest 2004; 114:1136-45.

Kaul DK, Liu XD, Fabry ME, Nagel RL. 92. Impaired nitric oxide-mediated vasodila-tion in transgenic sickle mouse. Am J Phy-siol Heart Circ Physiol 2000;278:H1799-H1806.

Morris CR, Kato GJ, Poljakovic M, et al. 93. Dysregulated arginine metabolism, hemo-lysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA 2005;294:81-90.

Gramaglia I, Sobolewski P, Meays D, 94. et al. Low nitric oxide bioavailability con-tributes to the genesis of experimental cerebral malaria. Nat Med 2006;12:1417-22.

Yeo TW, Lampah DA, Gitawati R, et 95. al. Impaired nitric oxide bioavailability and L-arginine reversible endothelial dysfunc-tion in adults with falciparum malaria. J Exp Med 2007;204:2693-704.

Villagra J, Shiva S, Hunter LA, Macha-96. do RF, Gladwin MT, Kato GJ. Platelet ac-tivation in patients with sickle disease, hemolysis-associated pulmonary hyperten-sion, and nitric oxide scavenging by cell-free hemoglobin. Blood 2007;110:2166-72.

Raghavachari N, Xu X, Harris A, et al. 97. Amplified expression profiling of platelet transcriptome reveals changes in arginine metabolic pathways in patients with sick-le cell disease. Circulation 2007;115:1551-62.

Ataga KI, Moore CG, Hillery CA, et al. 98. Coagulation activation and inflammation in sickle cell disease-associated pulmo-nary hypertension. Haematologica 2008; 93:20-6.

van Beers EJ, Spronk HM, Ten Cate H, 99. et al. No association of the hypercoagu-lable state with sickle cell disease related pulmonary hypertension. Haematologica 2008;93(5):e42-e44.

Westerman M, Pizzey A, Hirschman 100. J, et al. Microvesicles in haemoglobinopa-thies offer insights into mechanisms of hypercoagulability, haemolysis and the effects of therapy. Br J Haematol 2008; 142:126-35.

Setty BN, Rao AK, Stuart MJ. Throm-101. bophilia in sickle cell disease: the red cell connection. Blood 2001;98:3228-33.

Frei AC, Guo Y, Jones DW, et al. Vas-102. cular dysfunction in a murine model of severe hemolysis. Blood 2008;112:398-405.

De Castro LM, Jonassaint JC, Gra-103. ham FL, Ashley-Koch A, Telen MJ. Pulmo-nary hypertension associated with sickle cell disease: clinical and laboratory end-points and disease outcomes. Am J Hema-tol 2008;83:19-25.

Ataga KI, Moore CG, Jones S, et al. 104. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Br J Haematol 2006;134:109-15.

Ambrusko SJ, Gunawardena S, Saka-105. ra A, et al. Elevation of tricuspid regurgi-tant jet velocity, a marker for pulmonary hypertension in children with sickle cell disease. Pediatr Blood Cancer 2006;47:907-13.

Liem RI, Young LT, Thompson AA. 106. Tricuspid regurgitant jet velocity is associ-ated with hemolysis in children and young adults with sickle cell disease evaluated for pulmonary hypertension. Haemato-logica 2007;92:1549-52.

Pashankar FD, Carbonella J, Bazzy-107. Asaad A, Friedman A. Prevalence and risk

factors of elevated pulmonary artery pres-sures in children with sickle cell disease. Pediatrics 2008;121:777-82.

Onyekwere OC, Campbell A, Teshome 108. M, et al. Pulmonary hypertension in chil-dren and adolescents with sickle cell dis-ease. Pediatr Cardiol 2008;29:309-12.

Machado RF, Gladwin MT. Chronic 109. sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Br J Haema-tol 2005;129:449-64.

Castro OL, Hoque M, Brown BD. Pul-110. monary hypertension in sickle cell dis-ease: cardiac catheterization results and survival. Blood 2003;101:1257-61.

Ataga KI, Sood N, De Gent G, et al. 111. Pulmonary hypertension in sickle cell dis-ease. Am J Med 2004;117:665-9.

Machado RF, Anthi A, Steinberg 112. MH, et al. N-terminal pro-brain natriuret-ic peptide levels and risk of death in sick-le cell disease. JAMA 2006;296:310-8.

McQuillan BM, Picard MH, Leavitt 113. M, Weyman AE. Clinical correlates and reference intervals for pulmonary artery systolic pressure among echocardiograph-ically normal subjects. Circulation 2001; 104:2797-802.

Machado RF, Kyle Mack A, Martyr S, 114. et al. Severity of pulmonary hypertension during vaso-occlusive pain crisis and exer-cise in patients with sickle cell disease. Br J Haematol 2007;136:319-25.

Mekontso Dessap A, Leon R, Habibi 115. A, et al. Pulmonary hypertension and cor pulmonale during severe acute chest syn-drome in sickle cell disease. Am J Respir Crit Care Med 2008;177:646-53.

Sachdev V, Machado RF, Shizukuda Y, 116. et al. Diastolic dysfunction is an indepen-dent risk factor for death in patients with sickle cell disease. J Am Coll Cardiol 2007; 49:472-9.

Hayag-Barin JE, Smith RE, Tucker 117. FC Jr. Hereditary spherocytosis, thrombo-cytosis, and chronic pulmonary emboli: a case report and review of the literature. Am J Hematol 1998;57:82-4.

Vichinsky EP. Pulmonary hyperten-118. sion in sickle cell disease. N Engl J Med 2004;350:857-9.

Taylor JG IV, Nolan VG, Mendelsohn 119. L, Kato GJ, Gladwin MT, Steinberg MH. Chronic hyper-hemolysis in sickle cell ane-mia: association of vascular complications and mortality with less frequent vasooc-clusive pain. PLoS One 2008;3(5):e2095.Copyright © 2008 Massachusetts Medical Society.

collections of articles on the journal’s web site

The Journal’s Web site (www.nejm.org) sorts published articles into more than 50 distinct clinical collections, which can be used as convenient

entry points to clinical content. In each collection, articles are cited in reverse chronologic order, with the most recent first.



pulmonary complications of sickle cell

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